The technical field of this invention is prosthetic surgery and cell culturing. In particular, the invention pertains to methods and implantable urological structures formed on biocompatible artificial matrices for the reconstruction or repair of urological structures.
Shortage of native urothelium places significant constraints on the success of surgical reconstruction in a wide variety of urologic conditions. Investigators have recognized this problem and have looked for alternatives for urothelial replacement. A variety of natural tissues, such as omentum and seromuscular grafts, and synthetic materials, such as polyvinyl sponge and Teflon, have been tried in experimental and clinical settings.
Unfortunately, these attempts have not produced satisfactory structural and functional replacement. Synthetic materials alone cannot replace selective transport functions of mucosal tissue and commonly are lithogenic in the urinary tract.
Bowel tissue has been used for urinary tract reconstruction for many years, however it is also associated with numerous complications. These include metabolic abnormalities, such as hyperchloremic metabolic acidosis arising from electrolyte reabsorption, infection, perforation, stone formation, increased mucous production, diverticular formation, and malignancy. Despite these problems, incorporation of intestinal segments into the urinary system has increased because of the lack of a suitable alternative.
A homologous substitute for urothelial tissues would be ideal. Recent work involving hypospadias reconstruction using bladder mucosal grafts demonstrates the potential of autologous replacement. See, for example, Hendren and Reda, Vol. 21 J. Pediatric Surgery, pp. 181-192 (1986) and Ransley et al., Vol. 58 Brit. J. Urology, pp.331-333 (1986). However, the limited availability of urothelial tissue for patients requiring major reconstruction involving the kidney, ureter, bladder or urethra generally precludes its use.
The use of reconstructed sheets of autologous urothelium in urinary tract reconstruction would be ideal for a variety of surgical procedures and would have the added advantage of avoiding immunologic rejection. Autologous skin keratinocytes have been used successfully in the treatment of extensive burn wounds. See, for example, Green et al., Vol. 76 Proc. Nat'l. Acad. Sci. pp. 5665-5668 (1979) and Burke et al., Vol. 194 Ann, Surgery, pp. 413-428 (1981). Keratinocytes derived from the urethral meatus have also been used in urethral grafts for hypospadias repair in humans as described in Romagnoli et al, Vol. 323 New England J. Medicine, pp. 527-530 (1990).
U.S. Ser. No. 679,177 entitled "Chimeric Neomorphogenesis Of Organs By Controlled Cellular Implantation Using Artificial Matrices" filed Mar. 26, 1991, and U.S. Ser. No. 933,018 entitled "Chimeric Neomorphogenesis Of Organs Using Artificial Matrices" filed Nov. 20, 1986, by Joseph P. Vacanti and Robert S. Langer, herein incorporated by reference, describe methods and means whereby cells having a desired function are grown on polymer scaffolding using cell culture techniques, followed by transfer of the cell polymer scaffold into a patient at a site appropriate for attachment, growth and function after attachment and equilibration to produce a functional organ equivalent. Success depends on the ability of the implanted cells to attach to the surrounding environment and to stimulate angiogenesis. Nutrients and growth factors are supplied during cell culture allowing for attachment, survival or growth as needed.
After the structure is implanted and growth and vascularization take place, the resulting organoid is a chimera formed of parenchymal elements of the donated tissue and vascular and matrix elements of the host. The polymer scaffolding used for the initial cell culture is constructed of a material which degrades over time and is, therefore, not present in the chimeric organ. Vascular ingrowth following implantation allows for normal feedback mechanisms controlling the soluble products of the implanted cells. The preferred material for forming the matrix or support structure is a biodegradable, artificial polymer, for example, polyglycolic acid, polyorthoester or polyanhydride, which is degraded by hydrolysis at a controlled rate and reabsorbed.
These materials provide the maximum control of degradability, manageability, size and configuration. In some embodiments, these materials are overlaid with a second material, such as gelatin or agarose, to enhance cell attachment. The polymer matrix must be configured to provide both adequate sites for attachment and adequate diffusion of nutrients from the cell culture to maintain cell viability and growth until the matrix is implanted and vascularization has occurred. The preferred structure for organ construction is a branched, fibrous, tree-like structure formed of polymer fibers having a high surface area which results in a relatively shallow concentration gradient of nutrients, wastes and gases so as to produce uniform cell growth and proliferation.
U.S. Ser. No. 933,018 and U.S. Ser. No. 679,177 disclose several examples of the successful culturing and implantation of hepatocytes, intestine, and pancreas cells, with subsequent normal function, including production and secretion of bioactive molecules. Examples of such molecules include growth hormone from pituitary cells, insulin and glycogen from pancreatic cells and clotting factors from liver cells. As described in these applications, however, there is a need for a different type of functioning "organ," one which provides primarily a structural function. Examples of types of cells which are useful in these applications include cartilage, bone and muscle cells.
It is an object of the present invention to provide a method and means for designing, constructing and utilizing artificial matrices as temporary scaffolding for cellular growth and implantation of urological structures.
It is a further object of the invention to provide biodegradable, non-toxic matrices which can be utilized for cell growth, both in vitro and in vivo, as supports for urological structures.
It is a still further object of the invention to provide biodegradable, non-toxic matrices which can be utilized for cell growth both in vitro and in vivo, to replace or to repair urological structures
It is another object of this invention to provide an in vitro system in which cells will retain their normal morphology and cell function.